WO2018130948A9 - Composition de tapentadol pour la voie nasale - Google Patents

Composition de tapentadol pour la voie nasale Download PDF

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Publication number
WO2018130948A9
WO2018130948A9 PCT/IB2018/050148 IB2018050148W WO2018130948A9 WO 2018130948 A9 WO2018130948 A9 WO 2018130948A9 IB 2018050148 W IB2018050148 W IB 2018050148W WO 2018130948 A9 WO2018130948 A9 WO 2018130948A9
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Prior art keywords
tapentadol
human
unit dose
composition
dose
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PCT/IB2018/050148
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English (en)
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WO2018130948A1 (fr
Inventor
Jaya Abraham
Vivek Mishra
Vipul MITTAL
Kiran Chaudhari
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Torrent Pharmaceuticals Limited
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Priority to CN201880006573.1A priority Critical patent/CN110191708A/zh
Application filed by Torrent Pharmaceuticals Limited filed Critical Torrent Pharmaceuticals Limited
Priority to EP18704591.9A priority patent/EP3568126B1/fr
Priority to DK18704591.9T priority patent/DK3568126T3/da
Priority to PL18704591.9T priority patent/PL3568126T3/pl
Priority to HRP20240030TT priority patent/HRP20240030T1/hr
Priority to RS20231279A priority patent/RS65027B1/sr
Priority to SI201831051T priority patent/SI3568126T1/sl
Priority to FIEP18704591.9T priority patent/FI3568126T3/fi
Priority to LTEPPCT/IB2018/050148T priority patent/LT3568126T/lt
Priority to BR112019014408A priority patent/BR112019014408A2/pt
Publication of WO2018130948A1 publication Critical patent/WO2018130948A1/fr
Priority to PH12019501607A priority patent/PH12019501607A1/en
Publication of WO2018130948A9 publication Critical patent/WO2018130948A9/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • compositions for nasal administration comprising tapentadol, their preparation and their use in the treatment of pain.
  • Tapentadol is 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol.
  • a particularly preferred form is the hydrochloride salt, 3-[(lR,2R)-3-(dimethylamino)-l- ethyl-2-methylpropyl]phenol monohydrochloride.
  • Tapentadol is highly soluble drug and its solubility is pH dependent. It is considered as BCS class - I drug.
  • Tapentadol hydrochloride may be depicted structurally as follows.
  • Tapentadol is a centrally acting analgesic having both m-opioid receptor agonist and noradrenalin (norepinephrine) reuptake inhibition activity with minimal serotonin reuptake inhibition.
  • This dual mode of action makes tapentadol particularly useful in the treatment of both nociceptive pain and neuropathic pain.
  • Clinical trial evidence in acute and chronic non-cancer pain, cancer related pain and neuropathic pain supports an opioid-sparing effect that reduces some of the typical opioid-related adverse effects. Specifically, the reduction in treatment-emergent gastrointestinal adverse effects for tapentadol compared with equi- analgesic pure m-opioid receptor agonist results in improved tolerability and adherence to therapy.
  • U.S. Patent No. 6,248,737 discloses tapentadol and its hydrochloride salt. Tapentadol is available commercially as a brand name NUCYNTA ® as 50mg, 75mg and 1 OOmg (free base equivalent) oral tablet, indicated for the relief of moderate to severe acute pain.
  • tapentadol results in low bioavailability (32%) because of extensive first-pass metabolism where about 97% of the administered tapentadol is metabolized. None of the metabolites contributes to the analgesic activity. Lipid solubility of tapentadol is approximately 2.8, which is comparatively low. Being an opioid analgesic, tapentadol is useful for the treatment of severe pain such as post-operative pain, cancer pain, etc. In such cases nausea and vomiting is a frequently associated problem, and thus, poor patient compliance is seen with oral administration.
  • oral formulations are inadequate because absorption occurs at least 45 minutes after administration, which is not suitable in the treatment of breakthrough pain, as this delay in absorption is typically longer than the episode of breakthrough pain.
  • the maximum serum concentration of tapentadol is typically observed at around 1.25 hours after oral dosing.
  • the bitter taste of tapentadol is not patient friendly, and contributes to poor patient compliance.
  • opioids are known to show higher inter-subject variability (Clinical
  • U.S. Patent Application Publication No. 2006/0110333 discloses a composition for nasal absorption of opioid comprises calcium carbonate and/or calcium phosphate having particle size of up to 500 pm, with lower risk of developing side effects as compared to oral route.
  • U.S. Patent No. 5,629,011 discloses a composition for nasal administration comprises polar metabolite of opioid analgesic consists of glucoronides and ethereal sulphates of opioid analgesics.
  • U.S. Patent Application Publication No. 2010/0227921 discloses that tapentadol is associated with high inter-patient variability and therefore a uniform patient response may be lacking. Therefore, to overcome the problems, amino acids and peptide carbamate pro drugs of tapentadol are prepared.
  • U.S. Patent Application Publication No. 2014/0170209 discloses a nasal composition comprising tapentadol or its pharmaceutically acceptable salts and at least one nasal carrier. It is well known to the skilled person that apart from many factors, lipid solubility play crucial role in the absorption of drug through nasal mucosa. Drugs with high lipophilicity have higher tendency to get absorbed through nasal mucosa compared to almost negligible absorption of low lipophilicity drugs. It has been tested that, intranasal formulations of low lipophilicity drugs like morphine gives less bioavailability as compared to intravenous administration, when given in solution form. Therefore they are required to be given with agent like chitosan which provides longer time for drug transport across the nasal membrane, before the formulation is cleared by the mucociliary clearance mechanism.
  • the information disclosed herein is based on the observation that comparable tapentadol pharmacokinetic parameters may be achieved by intranasal administration of a lower tapentadol unit dose in a human when compared to oral administration of a higher tapentadol unit dose of an immediate release dosage form.
  • a unit dose comprising: tapentadol or a pharmaceutically acceptable salt thereof in an amount that is equivalent to about 19.3 mg tapentadol free base; and at least one nasal carrier; wherein after intranasal administration to the human a tapentadol mean Cmax -value achieved by said unit dose is equivalent to or greater than a tapentadol mean Cmax-value achieved by orally administering to the human an immediate release composition comprising tapentadol or a pharmaceutically acceptable salt thereof in an amount that is equivalent to 50 mg tapentadol free base.
  • FIG. 1 displays the mean plasma concentration (ng/mL) for Ex. 3 formulation at Dose Level 3S (17.5 mg/70 pL), Ex. 2 formulation at Dose Level 2S (22.5 mg/lOO pL), and Comp. Ex. 4 Oral-50 mg (free base equivalent).
  • FIG. 2 displays the mean plasma concentration (ng/mL) for Ex. 3 formulation at Dose Level 3B (17.5 mg/70 pL)*2 (administered to each nostril), Ex. 2 formulation at Dose Level 2B (22.5 mg/l00pL)*2 (administered to each nostril)), and Comp. Ex. 3 Oral 100 mg (free base equivalent).
  • compositional ingredient that is not preceded by the term "about” or“mostly about” does not mean that there is no variance for the stated term, as one of ordinary skill would understand that there is always some possibility of a degree of variability generally associated with experimental error.
  • a "unit dose” can be filled in a vial or container which by using suitable nasal spray can be administered to a human. It is possible that a vial may contain volume of composition that has multiple "unit doses” and delivers unit dose in single or multiple sprays.
  • administration refers to administration of a unit dose of a composition described herein to a human.
  • unit dose can be administered in a single spray to one nostril.
  • unit dose can be administered in a single spray to each nostril, which is synonymous with administration to both nostrils.
  • the unit dose may be administration over repeated time intervals, as needed.
  • immediate release composition comprising tapentadol
  • tapentadol refers to Nucynta® for oral administration.
  • the concentration unit "% w/v" is a measure of the weight amount of a specified ingredient based on the total volume of the composition.
  • the pharmaceutically acceptable salts of tapentadol are acid addition salts wherein acid is selected from hydrochloric acid, hydrobromic acid, embonic acid, (2S,3S)- dibenzoyltartaric acid, dibenzoyltartaric acid, sebacic acid, l-hydroxy- naphthoic acid, phosphoric acid, L-(+)-tartaric acid, lysinic acid, L-lysinic acid, D-(+)- malic acid, 4-methylbenzenesulfonic acid, ethanesulfonic acid, benzoic acid, cinnamic acid, L-(+)-lactic acid, S-(+)-mandelic acid, (+)-camphor- 10- sulfonic acid, gluconic acid, L-(+)-ascorbic acid, ascorbic acid, palmitic acid, naphthalene- l,5-disulfonic acid, hexanoic acid, o
  • composition as used herein is defined as a solution, suspension, or dispersion.
  • Crystal growth inhibitor as used herein is defined as an agent, which facilitates formation of a homogenous nasal composition of tapentadol and prevents crystal formation.
  • a unit dose comprising: tapentadol or a pharmaceutically acceptable salt thereof in an amount that is equivalent to about 19.3 mg tapentadol free base; and at least one nasal carrier; wherein after intranasal administration to the human a tapentadol mean Cmax-value achieved by said unit dose is equivalent to or greater than a tapentadol mean Cmax-value achieved by orally administering to the human an immediate release composition comprising tapentadol or a pharmaceutically acceptable salt thereof in an amount that is equivalent to 50 mg tapentadol free base.
  • A2 The unit dose according to Al, wherein intranasal administration of the unit dose to the human provides tapentadol mean Cmax-value that ranges from about 40 ng/mL to about 65 ng/mL.
  • A3 The unit dose according to Al, wherein a ratio of the tapentadol mean Cmax- value achieved by said intranasal administration of the unit dose to the tapentadol mean Cmax-value achieved by said oral administration ranges from about 1.0 to about 2.0.
  • A4 The unit dose according to Al, wherein intranasal administration of the unit dose to the human provides tapentadol mean AUCo e-value that ranges from about 115 hr*ng/mL to about 182 hr*ng/mL.
  • A5 The unit dose according to Al, wherein a ratio of the tapentadol mean AUCo-6- value achieved by said intranasal administration of the unit dose to the tapentadol mean AUCo- 6 -value achieved by said oral administration ranges from about 0.9 to about 1.7.
  • A6 The unit dose according to Al, wherein intranasal administration of the unit dose to the human provides the mean Tmax-value about 1 hr or less.
  • A8 The unit dose according to Al, wherein the immediate release composition comprises tapentadol hydrochloride.
  • a unit dose comprising: tapentadol or a pharmaceutically acceptable salt thereof in an amount that is equivalent to about 19.3 mg tapentadol free base; and at least one nasal carrier; wherein after intranasal administration to each nostril of the human a tapentadol mean Cmax-value achieved by said unit dose is equivalent to or greater than a tapentadol mean Cmax-value achieved by orally administering to a human an immediate release composition comprising tapentadol or a pharmaceutically acceptable salt thereof in an amount that is equivalent to about 100 mg tapentadol free base.
  • the unit dose according to B 1 wherein intranasal administration of the unit dose to each nostril of the human provides a tapentadol mean Cmax-value that ranges from about 98 ng/mL to about 155 ng/mL.
  • a unit dose comprising: tapentadol or a pharmaceutically acceptable salt thereof in an amount that is equivalent to about 19.3 mg tapentadol free base; and at least one nasal carrier, wherein the therapeutic efficacy of tapentadol achieved by intranasally administering to one nostril or both nostrils said unit dose in a human for the treatment of pain is equivalent to the therapeutic efficacy achieved by orally administering to a human an immediate release composition comprising tapentadol or a pharmaceutically acceptable salt thereof in an amount that is equivalent to about 50 mg and about 100 mg tapentadol free base, respectively.
  • a method of treating pain in a human in need thereof which comprises: intranasally administering to the human the unit dose of C 1.
  • a method of treating pain in a human in need thereof which comprises: intranasally administering to each nostril of the human the unit dose of C 1.
  • a method of treating pain in a human in need thereof which comprises: intranasally administering to the human a dose comprising tapentadol or a pharmaceutically acceptable salt thereof; wherein the amount of tapentadol in said dose is equivalent to about
  • a tapentadol mean Cmax-value achieved by said intranasal administration is equivalent to or greater than a tapentadol mean Cmax-value achieved by orally administering to a human an immediate release composition comprising tapentadol or a pharmaceutically acceptable salt thereof in an amount that is equivalent to 50 mg tapentadol free base.
  • D2 The method of D 1 comprising intranasally administering the dose to the human, wherein the tapentadol mean Cmax-value achieved by said intranasal administration ranges from about 40 ng/mL to about 65 ng/mL.
  • D3 The method of Dl comprising intranasally administering the dose to the human, wherein a ratio of the tapentadol mean Cmax-value achieved by said intranasal administration to the tapentadol mean Cmax-value achieved by said oral administration ranges from about 1.0 to about 2.0.
  • D4 The method of Dl comprising intranasally administering the dose to each nostril of the human, wherein the tapentadol mean Cmax-value achieved by said intranasal administration ranges from about 98 ng/mL to about 155 ng/mL.
  • D5 The method of D4 comprising intranasally administering the dose to each nostril of the human, wherein a ratio of the tapentadol mean Cmax-value achieved by said intranasal administration to the tapentadol mean Cmax-value achieved by said oral administration ranges from about 2.5 to about 5.0.
  • D6 The method of D 1 comprising intranasally administering the dose to the human, wherein the Tmax-value achieved by said intranasal administration is less than about 1 hr.
  • D7 The method of D 1 comprising intranasally administering the dose to the human, wherein the Tmax-value achieved by said intranasal administration ranges from about 0.2 hr to about 0.8 hr.
  • D8 The method of D 1 comprising intranasally administering the dose to the human, wherein the tapentadol mean AUCo-6-value achieved by said intranasal administration ranges from about 115 hr*ng/mL to about 182 hr*ng/mL.
  • D9 The method of D 1 comprising intranasally administering the dose to the human, wherein a ratio of the tapentadol mean AUCo e value achieved by said intranasal administration to the tapentadol mean AUCo-6- value achieved by said oral administration ranges from about 0.9 to about 1.7.
  • D 10. The method of D 1 comprising intranasally administering the dose to each nostril of the human, wherein the tapentadol mean AUCo e-value achieved by said intranasal administration ranges from about 230 hr*ng/mL to about 365 hr*ng/mL.
  • Dl l The method of D 1 comprising intranasally administering the dose to each nostril of the human, wherein a ratio of the tapentadol mean AUCo e-value achieved by said intranasal administration to the tapentadol mean AUCo e value achieved by said oral administration ranges from about 1.5 to about 3.5.
  • a method of treating pain in a human in need thereof which comprises: intranasally administering to each nostril of the human a dose comprising tapentadol or a pharmaceutically acceptable salt thereof; wherein the amount of tapentadol in the dose is equivalent to about 19.3 mg tapentadol free base; and wherein after administration of the dose to each nostril a tapentadol mean Cmax-value achieved by said intranasal administration is equivalent to or greater than a tapentadol mean Cmax-value achieved by orally administering to a human an immediate release composition comprising tapentadol or a pharmaceutically acceptable salt thereof in an amount that is equivalent to 100 mg tapentadol free base.
  • An intranasal composition for treating pain in a human which provides a dose reduction of tapentadol compared to an immediate release oral composition comprising a therapeutically effective dose of tapentadol or a pharmaceutically acceptable salt thereof, the intranasal composition comprising: a therapeutically effective dose of tapentadol or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable nasal carrier; wherein the ratio of the amount of tapentadol, based on the amount of tapentadol free base, in the intranasal dose to the amount of tapentadol, based on the amount of tapentadol free base, in the oral dose is selected from the group consisting of about 1 : 1.5 or less, about 1 :2 or less, about 1 :2.5 or less, about 1:3 or less, and about 1 :3.5 or less; and wherein the intranasal dose and the oral dose, when administered to the human, exhibit substantially equivalent bioavailability.
  • F2 The composition according to Fl,
  • composition according to Fl wherein the amount of tapentadol, based on the amount of tapentadol free base, in the oral dose is from about 50 to about 150 mg, or from about 50 to about 100 mg, or from about 50 to about 75 mg.
  • each of the intranasal composition and the oral composition comprises tapentadol hydrochloride
  • the amount of tapentadol hydrochloride in the oral dose is about 58 to 117 mg
  • the amount of tapentadol hydrochloride in the intranasal dose is selected from the group consisting of about 15 to about 20 mg, about 20 to about 22.5 mg, about 22.5 to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to 40 mg, about 40 mg to 45 mg and about 45 mg to 50 mg, and wherein the oral composition is an immediate release composition.
  • composition according to F 1 wherein the intranasal composition comprises tapentadol hydrochloride and a nasal carrier.
  • composition according to Fl wherein the intranasal composition is for providing relief of moderate to severe pain, preferably acute pain.
  • composition according to Fl wherein the immediate release oralcomposition comprises tapentadol hydrochloride.
  • Embodiment G Gl An intranasal composition for treating pain in a human that provides substantially equivalent therapeutic efficacy to the therapeutic efficacy provided by an immediate release oral composition comprising a therapeutically effective dose of tapentadol or a pharmaceutically acceptable salt thereof, the intranasal composition comprising: a therapeutically effective dose of tapentadol or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable nasal carrier; wherein the ratio of the amount of tapentadol, based on the amount of tapentadol free base, in the intranasal dose to the amount of tapentadol, based on the amount of tapentadol free base, in the oral dose is selected from the group consisting of about 1 : 1.5 or less, about 1 :2 or less, about 1 :2.5 or less, about 1 :3 or less, and about 1 :3.5 or less; and wherein the intranasal dose and the oral dose, when administered to the human, exhibit substantially equivalent bioavailability.
  • composition according to Gl, wherein the amount of tapentadol, based on the amount of tapentadol free base, in the oral dose is from about 50 to about 150 mg, or from about 50 to about 100 mg, or from about 50 to about 75 mg.
  • each of the intranasal composition and the oral composition comprises tapentadol hydrochloride
  • the amount of tapentadol hydrochloride in the oral dose is about 58 to about 117 mg and the amount of tapentadol hydrochloride in the intranasal dose is selected from the group consisting of about 15 to about 20 mg, about 20 to about 22.5 mg, about 22.5 to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to 40 mg, about 40 mg to about 45 mg and about 45 mg to about 50 mg, and wherein the oral composition is an immediate release composition.
  • composition according to Gl wherein the intranasal composition comprises tapentadol hydrochloride and a nasal carrier.
  • G5. The composition according to Gl, wherein the bioavailability of the intranasal dose and the oral dose are measured after single dose administration to human.
  • G6 The composition according to Gl, wherein the intranasal composition is for providing relief of moderate to severe pain, preferably acute pain.
  • composition according to Gl, wherein the immediate release oral composition comprises tapentadol hydrochloride.
  • kits for administration of tapentadol or a pharmaceutically acceptable salt thereof to a human to treat pain while providing a dose reduction of tapentadol compared to an immediate release oral composition comprising a therapeutically effective dose of tapentadol or a pharmaceutically acceptable salt thereof comprising: (i) a composition for intranasal administration comprising therapeutically effective dose of tapentadol or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable nasal carrier; and (ii) a container equipped with a spray pump adapted to deliver the composition into one nostril or each nostril of the human, wherein the container is configured such that it delivers the therapeutically effective dose in one spray or in two sprays, and wherein the ratio of the amount of tapentadol, based on the amount of tapentadol free base, in the intranasal dose to the amount of tapentadol, based on the amount of tapentadol free base, in the oral dose is selected from the group consisting of
  • kits according to Hl wherein the spray pump is a metered multi-dose spray pump that is adapted to deliver the therapeutically effective intranasal dose in one spray.
  • H3. The kit according to H 1 , wherein the amount of tapentadol, based on the amount of tapentadol free base, in the oral dose is from about 50 to about 150 mg, or from about 50 to about 100 mg, or from about 50 to about 75 mg.
  • each of the intranasal composition and the oral composition comprises tapentadol hydrochloride
  • the amount of tapentadol hydrochloride in the oral dose is about 58 to about 117 mg and the amount of tapentadol hydrochloride in the intranasal dose is selected from the group consisting of about 15 to about 20 mg, about 20 to about 22.5 mg, about 22.5 to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg and about 45 mg to about 50 mg, and wherein the oral composition is an immediate release composition.
  • kits according to Hl wherein the intranasal dose provides relief of moderate to severe pain, preferably acute pain.
  • kits according to Hl wherein the composition comprises an aqueous solution of tapentadol or tapentadol hydrochloride.
  • kits according to HI wherein the bioavailability of the intranasal dose and the oral dose are measured after single dose administration to human.
  • kits according to HI wherein the immediate release oral composition comprises tapentadol hydrochloride.
  • a method for treating pain in a human in need thereof which provides a dose reduction of tapentadol compared to the administration of an immediate release oral composition comprising a therapeutically effective dose of tapentadol or a pharmaceutically acceptable salt thereof, the method comprising: intranasally administering to said human a composition comprising a therapeutically effective dose of tapentadol or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable nasal carrier; wherein the ratio of the amount of tapentadol, based on the amount of tapentadol free base, in the intranasal dose to the amount of tapentadol, based on the amount of tapentadol free base, in the oral dose is selected from the group consisting of about 1 : 1.5 or less, about 1 :2 or less, about 1 :2.5 or less, about 1:3 or less, and about 1 :3.5 or less; and wherein the intranasal dose and the oral dose, when administered to the human, exhibit substantially equivalent bioava
  • the method according to II, wherein the amount of tapentadol, based on the amount of tapentadol free base, in the oral dose is from about 50 to about 150 mg, or from about 50 to about 100 mg, or from about 50 to about 75 mg.
  • each of the intranasal composition and the oral composition comprises tapentadol hydrochloride
  • the amount of tapentadol in the oral dose is about 58 to about 117 mg and the amount of tapentadol in the intranasal dose is selected from the group consisting of about 15 to about 20 mg, about 20 to about 22.5 mg, about 22.5 to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg and about 45 mg to about 50 mg
  • the oral composition is an immediate release composition.
  • the intranasal composition comprises tapentadol hydrochloride and a nasal carrier. 16. The method according to II, wherein the bioavailability of the intranasal dose and the oral dose are measured after single dose administration to human.
  • a method for treating pain in a human which provides therapeutic efficacy substantially equivalent to the therapeutic efficacy provided by the administration of an immediate release oral composition comprising a therapeutically effective dose of tapentadol or a pharmaceutically acceptable salt thereof comprising: intranasally administering to said human a composition comprising a therapeutically effective dose of tapentadol or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable nasal carrier; wherein the ratio of the amount of tapentadol, based on the amount of tapentadol free base, in the intranasal dose to the amount of tapentadol, based on the amount of tapentadol free base, in the oral dose is selected from the group consisting of about 1: 1.5 or less, about 1 :2 or less, about 1 :2.5 or less, about 1 :3 or less, and about 1 :3.5 or less; and wherein the intranasal dose and the oral dose.
  • J2 The method according to J2, wherein the amount of tapentadol, based on the amount of tapentadol free base, in the oral dose is from about 50 to about 150 mg, or from about 50 to about 100 mg, or from about 50 to about 75 mg.
  • each of the intranasal composition and the oral composition comprises tapentadol hydrochloride
  • the amount of tapentadol hydrochloride in the oral dose is about 58 to about 117 mg and the amount of tapentadol hydrochloride in the intranasal dose is selected from the group consisting of about 15 to about 20 mg, about 20 to about 22.5 mg, about 22.5 to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to 40 mg, about 40 mg to 45 mg and about 45 mg to about 50 mg, and wherein the oral composition is an immediate release composition.
  • intranasal composition comprises tapentadol hydrochloride and a nasal carrier.
  • J5 The method according to Jl, wherein the bioavailability of the intranasal dose and the oral dose are measured after single dose administration to human.
  • J6 The method according to Jl, wherein the method provides relief of moderate to severe pain, preferably acute pain.
  • a method of increasing the bioavailability of tapentadol in a human comprising intranasally administering to said human a pharmaceutical composition comprising a therapeutically effective dose of tapentadol or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable nasal carrier, wherein the bioavailability of the intranasal dose is increased compared to the bioavailability of an equivalent dose of an immediate release oral composition comprising a therapeutically effective dose of tapentadol or a pharmaceutically acceptable salt thereof.
  • K2 The method according to Kl, wherein the ratio of the mean AUCo-6 of tapentadol after the intranasal administration to the mean AUCo- 6 of tapentadol after the oral administration is selected from the group consisting of at least about 1.5: 1, at least about 2:1, at least about 2.5:1, at least about 3: 1 and at least about 3.5: 1.
  • K4 The method according to Kl, wherein the mean AUCo- 6 of the intranasal dose and the mean AUCo-6 of the oral dose are measured after single dose administration to human.
  • immediate release oral composition comprises tapentadol hydrochloride.
  • unit dose, dose or therapeutically effective dose may comprise tapentadol hydrochloride in an amount that is equivalent to about 15 mg to about 20 mg of tapentadol free base or any value in between, including, for example 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5. up to 20.0mg.
  • compositions disclosed herein contain tapentadol or its pharmaceutically acceptable salt(s) in an amount equivalent to about 0.9 to about 49.9% w/v of tapentadol free base, or any values in between, including, for example, 1.0, 1.1, 1.2.,...up to 15, 15.1, 15.2,...up to 19.3, 19.4, 19.5,...up to 21.5, 21.6, 21.7,...up to 33.1, 33.2, 33.3, ...up to 49.9% w/v.
  • Compositions exemplified herein contain an amount of tapentadol free base of
  • compositions or unit dose according to any of the embodiment are comprised of a nasal carrier (or pharmaceutically acceptable nasal carrier) selected from a mucoadhesive agent, a solubilizer, a sweetener, a preservative, a flavoring agent, and a vehicle.
  • a nasal carrier or pharmaceutically acceptable nasal carrier selected from a mucoadhesive agent, a solubilizer, a sweetener, a preservative, a flavoring agent, and a vehicle.
  • mucoadhesive agent examples include, but are not limited to such as polyacrylic polymers like carbopols, polycarbophil, carboxymethylcellulose or its pharmaceutically acceptable salt, microcrystalline cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose (i.e., hypromellose), methylcellulose, poloxamers, pectin, xanthan gums, alginates, gelatin alone or in any combination thereof.
  • a preferred mucoadhesive agent is selected from hydroxypropylmethyl cellulose and carboxymethyl cellulose or its pharmaceutically acceptable salt.
  • Nasal compositions disclosed herein contain about 0.05 to about 5% w/v of a mucoadhesive agent or any values between, including, for example, 0.1, 0.15, 0.2, 0.25, 0.30, 0.35, 0.4,...up to 5% w/v.
  • An amount of a mucoadhesive agent exemplified herein is about 0.1% w/v of hydroxypropyl methyl cellulose.
  • solubilizers include, but are not limited to d-alpha tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), macrogol (15)-hydroxystearate (Solutol HS 15), polyoxyethylene-polyoxypropylene copolymer (Poloxamer, Pluronic, such as poloxamer 188), PEO-PLLA diblock copolymer, PEG- PLGA-PEG triblock, copolymer, cyclodextrins, hydroxypropyl betadex, polyoxyethylene castor oil derivatives, povidone,, sulfobutylether-b-cyclodextrin, tricaprylin, triolein, glyceryl monostearate, sorbitan esters (sorbitan fatty acid esters), polyoxyethylene fatty acid esters, polysorbate 80, polysorbate 20 or macrogol- 15 -hydroxyster ate, alone or in combination thereof.
  • solubilizers include, but are not
  • a preferred solubilizer is polyoxyethylene-polyoxypropylene copolymer, such as, poloxamer 188. It is observed that increase in concentration of the tapentadol in the solution leads to formation of crystals, when stored for extended duration (for more than 3 days). This makes the formulation non-homogeneous and therefore non-suitable for nasal administration. This crystal growth may further lead to altered therapeutic effect of the drug.
  • the solubilizer may function as a crystal growth inhibitor, which permits manufacture of a composition having a higher concentration and that permits long term storage.
  • Nasal compositions disclosed herein contain from about 0.2 to about 10.0% w/v of a solubilizer or any values between, including, for example, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, ...up to 10.0% w/v.
  • An amount of a solubilizer exemplified herein is about 0.6% w/v.
  • the sweetener is selected from the group comprising of aspartame, saccharin sodium, acesulfame potassium, dried invert sugar, dextrose, glucose, fructose, galactose, levulose, maltose, neotame, sucralose, neotame and mixture thereof.
  • Preferred sweetener is sucralose.
  • Another preferred sweetener is neotame.
  • Nasal compositions disclosed herein contain from about 0.1% to about 1% of a sweetener or any values between, including, for example, 0.2, 0.3, 0.4, 0.5, 0.6, ...up to 1.0% w/v.
  • An amount of a sweetener exemplified herein is about 0.5% w/v.
  • Suitable preservatives include, but are not limited to, benzalkonium chloride, sodium benzoate, methyl, ethyl, propyl or butyl paraben, benzyl alcohol, phenylethyl alcohol, benzethonium chloride, chlorobutanol, potassium sorbate or combination thereof.
  • a preferred preservative is benzalkonium chloride.
  • Nasal compositions disclosed herein contain from about 0.01 to about 1% w/v of a preservative or any values between, including, for example, 0.02, 0.03, 0.04, 0.05,...up to 0.1, and 0.2, 0.3, 0.4, 0.5, 0.6, up to 1% w/v.
  • An amount of a sweetener exemplified herein is about 0.5% w/v.
  • flavoring agent(s) include, but are not limited to flavor anise, flavor apple, flavor apricot, flavor Banana, flavor bitter mask, flavor buttermint, flavor citrus, flavor orange, flavor menthol mint, flavor mint, flavor peppermint, flavor spearmint, alone or in any combination thereof.
  • a preferred flavor is flavor spearmint.
  • Nasal compositions disclosed herein contain from about 0.01% w/v to about 0.5% w/v of a flavoring agent or any values between, including, for example, 0.02, 0.03, 0.04, 0.05, 0.6, 0.07, 0.08, 0.09, 0.10,... up to 0.5% w/v.
  • An amount of a flavoring agent exemplified herein is about 0.1% w/v.
  • vehicles examples include, but are not limited to, saline, water, dextrose or combinations thereof.
  • a preferred vehicle is purified water.
  • the amount of vehicle depends on the amounts of the other ingredients found in the nasal composition.
  • the amount of vehicle is a sufficient amount (q.s.) that is required to establish a specified volume.
  • the pH of compositions described herein may be about 3.0 to about 7.4 and ah values in between, including, for example, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7,... up to 7.4.
  • a preferred pH of compositions described herein may be about 4.5.
  • the pH may be adjusted using a pH adjusting agent, including, for example, hydrochloric acid or sodium hydroxide.
  • a buffering agent in an amount that preferably does not irritate the nasal mucosa.
  • a buffering agent includes an agent that resists changes to pH.
  • Exemplary buffering agents include, but are not limited to, salts of citrate, acetate, or phosphate.
  • More preferred buffering agents are selected from sodium citrate, sodium acetate, sodium phosphate, and/or combinations thereof.
  • the unit dose or composition according to any of the embodiment(s) disclosed herein comprising tapentadol or a pharmaceutically acceptable salt thereof in an amount equivalent to about 19.3 % w/v tapentadol free base and a nasal carrier, wherein the nasal carrier is selected from about 0.05 to about 5% w/v of a mucoadhesive agent; from about 0.2 to about 10.0% w/v of a solubilizer; from about 0.1% to about 1% of a sweetener; from about 0.01 to about 1% w/v of a preservative, from about 0.01% w/v to about 0.5% w/v of a flavoring agent, and a sufficient amount of a water vehicle.
  • unit dose or composition comprises mucoadhesive agent selected from hydroxypropylmethyl cellulose and carboxymethyl cellulose or its pharmaceutically acceptable salt
  • the solubilizer comprises a poloxamer
  • the sweetener selected from sucralose and neotame
  • preservative comprises benzalkonium chloride
  • the flavoring agent comprises a spearmint flavor.
  • unit dose or composition according to any of the embodiments comprises nasal carrier selected from about 0.1% w/v hydroxypropylmethyl cellulose, about 0.6% w/v of a poloxamer, about 0.5% w/v of a sweetener, about 0.02% w/v of a preservative, and a sufficient amount of a water vehicle.
  • compositions described herein provide a quick onset of action as compared to an immediate release oral composition, in which the Cmax can be achieved in a shorter period of time as compared to oral administration.
  • Composition or unit dose disclosed herein provides mean Cmax-value that ranges from about 40 ng/mL to about 65 ng/mL or about 98 ng/mL to about 155 ng/mL; mean AUCo e-value that ranges from about 115 hr*ng/mL to about 182 hr*ng/mL or about 230 hr*ng/mL to about 365 hr*ng/mL and Tmax-value about 1 hr or less.
  • compositions disclosed herein provide for a unit dose in a volume of from about 25 pL to about 150 pL, or any values between, including, for example, 30 pL, 35 pL, 40 pL,...up to 70 pL, 75 pL, 80 pL,...up to 100 pL, 105 pL, 110 pL,...up to 150 pL.
  • Exemplified embodiments described herein administer a unit dose of either about 70 pL or about 100 pL or about 140 pL, to one or both nostrils.
  • compositions or unit dose described herein when administered intranasally has a spray having an ovality ratio between about 1 to about 2, or between about 1 to about 1.5 or between about 1 to about 1.3 when measured at about 2.5 cm, and wherein the spray produces droplets of which less than about 10%, preferably less than about 5%, more preferably less than about 2%, have a diameter of less than about 10 pm.
  • compositions or unit dose described herein when administered intranasally has a spray comprising a mist of droplets of which less than about 10%, preferably less than about 5%, more preferably less than about 2%, have a diameter of less than about 10 pm, and wherein the droplets are characterized by (i) Dv(50) of between about 40 pm to about 150 pm, preferably between about 50 pm to about 120 pm; and/or (ii) Dv(90) of less than about 350 pm. Droplet size distribution is measured using Laser diffraction method with Spraytec®.
  • a kit described herein may further comprise instruction for use, for example in the form of an insert or label.
  • compositions or unit dose described herein may be useful for the treatment of pain, and particularly acute pain.
  • the acute pain is selected from but not limited to breakthrough cancer pain, dental pain or pain associated with the medical conditions which include day care surgeries, appendicectomy, cholecystectomy, nailing, plating, fixation of fractured bone, bums dressing, jejunostomy dressing and wound dressing.
  • compositions can be in the form of a dry powder with suitable particle size or can be in liquid form.
  • a unit dose or a composition is in liquid form, which can be a suspension, a solution or a dispersion.
  • the process comprises the step of mixing tapentadol or its pharmaceutically acceptable salt(s) with at least one nasal carrier. Tapentadol or its pharmaceutically acceptable salt(s) and nasal carrier can be mixed in any order to prepare final mixture, solution, suspension or dispersion.
  • a composition or a unit dose is prepared by mixing a mucoadhesive agent and a solubilizer to prepare a solution or a dispersion; adding tapentadol or its pharmaceutically acceptable salt with said solution or dispersion.
  • a suitable drying technique including freeze drying or spray drying.
  • compositions or unit dose described herein can be administered through a nasal spray or any suitable nasal applicator.
  • Nasal composition can be of multi dose container or unit dose container, preferably in multi dose container.
  • Packaging 3 100 pL _ 100 pL 100 pL and 70 pL 100 pL and 140 pL
  • VL5 2T5 25 mg/spray and 38.5 mg/spray and
  • the respective concentrations of tapentadol hydrochloride in the exemplified embodiments are: Ex. 1 (175 mg/mL), Ex. 2 (225 mg/mL), Ex. 3 (250 mg/mL), and Ex. 4 (385 mg/mL).
  • the respective concentrations of tapentadol (free base) in the exemplified embodiments are: Ex. 1 (150.3 mg/mL), Ex. 2 (193.2 mg/mL), Ex. 3 (214.6 mg/mL), and Ex. 4 (330.6 mg/mL).
  • Tump used Aptar 100 pL CPS pump (at 2.5 cm and 5 cm distances).
  • Tump used Aptar 140 pL CPS pump (at 2.5 cm and 5 cm distances).
  • DSD Droplet size distribution
  • the observed spray patterns for each composition shows that the ovality ratio is about 1 , which signifies that at different distances of administration the spray pattern remains the same, and which assures the effective distribution of droplets in nostril(s) and thus reducing the variability in absorption.
  • the observed droplet size distribution (DSD) values for each composition shows effective formation of droplet size. Generally, smaller droplets tend to deposit in the lower turbinate in nasal mucosa which is having slower clearance than middle and upper turbinate, for systemic delivery it is always preferable that maximum deposition to be carried out in middle turbinate.
  • DN bDose Normalized
  • dDN values calculated from 100 mg values using a proportion and propagating errors.
  • a 50-mg dose tapentadol free base is equivalent to 58.24-mg dose of tapentadol hydrochloride, while a lOO-mg dose of tapentadol free base is equivalent to H6.48-mg tapentadol hydrochloride.
  • Formulations were tested in human for the following objectives: (i) dose reduction from intranasal route in comparison to oral administration; (ii) effect of administration volume; (iii) effect of concentration; and (iv) effect of surface area.
  • PK pharmacokinetic
  • FIG. 1 displays the mean plasma concentration (ng/mL) after the administration of: (i) Ex. 3 formulation at Dose Level 3S, 17.5 mg tapentadol hydrochloride (equivalent to 15 mg tapentadol free base) administered to a single (S) nostril using a dosage volume of 70 pL; (ii) Ex. 2 formulation at Dose Level 2S, 22.5 mg tapentadol hydrochloride (equivalent to 19.3 mg tapentadol free base) administered to single (S) nostril using a dosage volume of 100 pL; and (iii) Comp. Ex. 4 (oral administration of immediate release composition containing 50 mg tapentadol free base).
  • Ex. 3 formulation at Dose Level 3S 17.5 mg tapentadol hydrochloride (equivalent to 15 mg tapentadol free base) administered to a single (S) nostril using a dosage volume of 70 pL
  • FIG. 2 displays the mean plasma concentration (ng/mL) after the administration of: (i) Ex. 3 formulation at Dose Level 3B, 17.5 mg tapentadol hydrochloride administered to both (B) nostrils using a dosage volume of 70 pL for each nostril (total dosage amount: 35 mg tapentadol hydrochloride (equivalent to 30 mg tapentadol free base); (ii) Ex.
  • the mean Cmax value achieved by intranasally administering Dose Level 2S is at least about two-times greater than the mean Cmax achieved by orally administering to a human a single dose of an immediate release composition comprising tapentadol or a pharmaceutically acceptable salt thereof in an amount that is equivalent to about 19.3 mg tapentadol free base. More specifically, the mean Cmax value achieved by intranasally administering Dose Level 2S is about three-times greater than the mean Cmax achieved by orally administering to a human a single dose of an immediate release composition comprising tapentadol or a pharmaceutically acceptable salt thereof in an amount that is equivalent to about 19.3 mg tapentadol free base.

Abstract

L'invention concerne une composition intranasale sous forme de dose unitaire, comprenant du tapentadol ou un sel pharmaceutiquement acceptable de ce dernier en une quantité équivalente à environ 19,3 mg de base libre de tapentadol; et au moins un support approprié à la voie nasale. Après administration intranasale chez l'humain, la valeur Cmax moyenne de tapentadol obtenue à l'aide de ladite dose unitaire est équivalente ou supérieure à la valeur Cmax moyenne de tapentadol obtenue par l'administration orale à l'humain d'une composition à libération immédiate comprenant du tapentadol ou un sel pharmaceutiquement acceptable de ce dernier en une quantité équivalente à 50 mg de base libre de tapentadol.
PCT/IB2018/050148 2017-01-11 2018-01-10 Composition de tapentadol pour la voie nasale WO2018130948A1 (fr)

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RS20231279A RS65027B1 (sr) 2017-01-11 2018-01-10 Nazalna kompozicija tapentadola
EP18704591.9A EP3568126B1 (fr) 2017-01-11 2018-01-10 Composition de tapentadol pour la voie nasale
DK18704591.9T DK3568126T3 (da) 2017-01-11 2018-01-10 Sammensætning af tapentadol nasal
PL18704591.9T PL3568126T3 (pl) 2017-01-11 2018-01-10 Donosowa kompozycja tapentadolu
HRP20240030TT HRP20240030T1 (hr) 2017-01-11 2018-01-10 Nazalni sastav tapentadola
CN201880006573.1A CN110191708A (zh) 2017-01-11 2018-01-10 他喷他多鼻用组合物
SI201831051T SI3568126T1 (sl) 2017-01-11 2018-01-10 Tapentadolni nazalni sestavek
BR112019014408A BR112019014408A2 (pt) 2017-01-11 2018-01-10 composição nasal de tapentadol
LTEPPCT/IB2018/050148T LT3568126T (lt) 2017-01-11 2018-01-10 Tapentadolio kompozicija vartojimui per nosį
FIEP18704591.9T FI3568126T3 (fi) 2017-01-11 2018-01-10 Nenään annosteltavia tapentadolikoostumuksia
PH12019501607A PH12019501607A1 (en) 2017-01-11 2019-07-09 Tapentadol nasal composition

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GB9202464D0 (en) 1992-02-05 1992-03-18 Danbiosyst Uk Composition for nasal administration
DE4426245A1 (de) 1994-07-23 1996-02-22 Gruenenthal Gmbh 1-Phenyl-3-dimethylamino-propanverbindungen mit pharmakologischer Wirkung
US20040115133A1 (en) 2000-05-10 2004-06-17 Wermeling Daniel P. Intranasal opioid compositions
CN1674903A (zh) 2002-07-11 2005-09-28 大鹏药品工业株式会社 经鼻吸收用组合物
GB0300531D0 (en) * 2003-01-10 2003-02-12 West Pharm Serv Drug Res Ltd Pharmaceutical compositions
US20100227921A1 (en) * 2009-03-03 2010-09-09 Shire Llc Amino acid and peptide carbamate prodrugs of tapentadol and uses thereof
US11413239B2 (en) 2011-07-20 2022-08-16 Torrent Pharmaceuticals Ltd. Pharmaceutical composition of tapentadol for nasal administration
CN103735500B (zh) * 2014-01-28 2016-01-20 江苏华泽医药科技有限公司 盐酸他喷他多注射液及其制备方法
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PH12019501607A1 (en) 2020-03-09
DK3568126T3 (da) 2024-01-15
HRP20240030T1 (hr) 2024-03-29
LT3568126T (lt) 2023-12-11
WO2018130948A1 (fr) 2018-07-19
BR112019014408A2 (pt) 2020-04-28
FI3568126T3 (fi) 2024-01-24
PL3568126T3 (pl) 2024-03-25
EP3568126A1 (fr) 2019-11-20
SI3568126T1 (sl) 2024-03-29

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